Hsa‐mir‐27a genetic variant contributes to gastric cancer susceptibility through affecting miR‐27a and target gene expression

Abstract

Aberrant microRNA (miRNA) expression is presently proposed to correlate with various human cancers and common single-nucleotide polymorphisms (SNP) at miRNA genes can influence the maturation of miRNAs or miRNA-mediated transcriptional regulation. However, whether miRNAs SNP alter gastric cancer susceptibility is still unclear. Here we investigated the possible role of a common A/G polymorphism (rs895819) within hsa-mir-27a in the development or progression of gastric cancer, and assessed the effect of rs895819 on the expression of miR-27a and its target gene Zinc finger and BTB domain containing 10 (ZBTB10). In the present case-control study, we found that subjects with the variant genotypes (AG + GG) showed a significantly increased risk of gastric cancer relative to AA carriers (adjusted odds ratio = 1.48, 95% confidence interval 1.06-2.05; P = 0.019). The elevated risk was especially evident in older subjects (age >58 years), men, nonsmokers and rural subjects. A significant association of hsamir-27a variant genotypes with lymph node metastasis was also observed. Further functional analyses indicated that variant genotypes might be responsible for elevated miR-27a levels and reduced ZBTB10 mRNA. Moreover, an inverse correlation was found between ZBTB10 and miR-27a levels. In conclusion, we were the first to show that a common polymorphism (rs895819) in hsa-mir-27a, by modulating miR-27a and ZBTB10 levels, acted as an important factor of the gastric cancer susceptibility. (Cancer Sci 2010; 101: 2241-2247 G astric cancer is one of the commonest malignant tumors in the world.(1) Of all the treatment modalities, only surgical resection may offer an opportunity for long-term survival. However, in most cases, curative resection of the tumor is impossible because of the advanced stage at the time of diagnosis.(2) In this regard, early detection of gastric cancer currently is the most important measure to decrease disease-associated mortality. Therefore, it appears very important to find novel diagnosis biomarkers to improve patient prognosis.MicroRNAs (miRNAs), a class of small endogenous noncoding RNA, negatively regulate post-transcriptional gene expression by directly cleaving target mRNA or by inhibiting their translation.(3) Although the underlying biological functions are not completely clear, it has been shown to play important roles in a variety of cellular processes including apoptosis, differentiation and cell proliferation.(4-6) Recent studies have identified that aberrant miRNAs expression correlated with various human cancers such as colon tumors, breast cancer, lung cancer, pancreatic cancer and gastric cancer. There is increasing evidence that single nucleotide polymorphisms (SNP) or mutations could make a significant contribution to disease susceptibility and outcome. The high degree of phylogenetic conservation in miRNA sequences determines that the functional variation in miRNAs may influence various biological processes. Therefore, a mutation or a SNP in miRNA genes might influence the transcrip...

Association between LMP2 and LMP7 gene polymorphisms and the risk of gastric cancer: A case-control study

“…Similar to other malignancies, the mechanism of gastric carcinogenesis involves a complex multi-stage and multi-factorial process that depends on gene-environment interactions (4). In previous epidemiological studies, genetic factors were demonstrated to play an important role in the development of gastric cancer (5)(6)(7)(8).…”

MicroRNA-27a regulates basal transcription by targeting the p44 subunit of general transcription factor IIH

“…Furthermore, many features of previously mentioned syndromes (i.e., chromosomal instability, cancer) can be explained by problems associated to chromosome segrega- tion and mitosis, which might result from improper p44 downregulation. In that regard, the overexpression of miR-27a in several cancer types has been proposed to promote oncogenic features, supporting that improper transcriptional shutdown/ inefficient DNA repair might lead to improper resolution of mitosis and cancer (32,(35)(36)(37).…”

Association Between the hsa-mir-27a Variant and Breast Cancer Risk: a Meta-analysis

“…In total, four studies fulfilled the inclusion criteria (Yang et al, 2010;Sun et al, 2010;Zhang et al, 2012;Catucci et al 2012) with 2763 cases and 3556 controls for hsa-mir-27a rs895819 polymorphism. The studies identified and their main characteristics are summarized in Table 1.…”

“…The studies identified and their main characteristics are summarized in Table 1. Among these publications, there were two studies of European descent (Yang et al, 2010;Zhang et al, 2012), two study of Asian descent (Sun et al, 2010;Catucci et al, 2012). All of the cases were histologically confirmed as breast cancer or Gastric cancer.…”